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WO2003063844A2 - Traitement de la polyarthrite rhumatoide - Google Patents

Traitement de la polyarthrite rhumatoide Download PDF

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Publication number
WO2003063844A2
WO2003063844A2 PCT/EP2003/000802 EP0300802W WO03063844A2 WO 2003063844 A2 WO2003063844 A2 WO 2003063844A2 EP 0300802 W EP0300802 W EP 0300802W WO 03063844 A2 WO03063844 A2 WO 03063844A2
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WO
WIPO (PCT)
Prior art keywords
formula
salt
rheumatoid arthritis
treatment
compound
Prior art date
Application number
PCT/EP2003/000802
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English (en)
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WO2003063844A3 (fr
Inventor
Heikki Joensuu
Original Assignee
Hyks-Instituutti Oy
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2003563538A priority Critical patent/JP4398731B2/ja
Priority to DE60321888T priority patent/DE60321888D1/de
Priority to BR0307286-0A priority patent/BR0307286A/pt
Priority to CA2473158A priority patent/CA2473158C/fr
Priority to DK03704474T priority patent/DK1471916T3/da
Priority to US10/502,534 priority patent/US20060264443A1/en
Priority to SI200331369T priority patent/SI1471916T1/sl
Priority to KR1020047011580A priority patent/KR101030416B1/ko
Priority to EP03704474A priority patent/EP1471916B1/fr
Application filed by Hyks-Instituutti Oy filed Critical Hyks-Instituutti Oy
Priority to NZ534137A priority patent/NZ534137A/en
Priority to MXPA04007309A priority patent/MXPA04007309A/es
Publication of WO2003063844A2 publication Critical patent/WO2003063844A2/fr
Publication of WO2003063844A3 publication Critical patent/WO2003063844A3/fr
Priority to ZA2004/05323A priority patent/ZA200405323B/en
Priority to IL162983A priority patent/IL162983A/en
Priority to NO20043585A priority patent/NO328255B1/no
Priority to HK05103443A priority patent/HK1072192A1/xx
Priority to US12/328,013 priority patent/US20090131382A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to the use of 4-(4-methylpiperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3- yl)pyrimidin-2-ylamino)phenyl]-benzamide (hereinafter: "COMPOUND I”) or a pharmaceutically acceptable salt thereof for the manufacture of pharmaceutical compositions for use in the treatment of inflammatory diseases especially rheumatoid arthritis (RA), to the use of COMPOUND I or a pharmaceutically acceptable salt thereof in the treatment of RA, to a method of treating warm-blooded animals including mammals, especially humans suffering from or susceptible to RA by administering to a said animal in need of such treatment an effective dose of COMPOUND I or a pharmaceutically acceptable salt thereof.
  • COMPOUND I 4-(4-methylpiperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3- yl)pyrimidin-2-ylamino)phenyl]-benzamide
  • COMPOUND I 4-(4
  • the invention also relates to a combination of COMPOUND I or a pharmaceutically acceptable salt thereof with one or more disease modifying arthritis rheumatoid drugs (DMARDs) to treat warmblooded animals including mammals, especially humans having or susceptible to RA.
  • DMARDs disease modifying arthritis rheumatoid drugs
  • Rheumatoid Arthritis is a common chronic debilitating disease that may affect the longevity of life.
  • the clinical course of RA is variable but it has become clear that the outcome of rheumatoid arthritis is much worse than was previously thought.
  • the range of presentation of RA is broad but the disease onset is insidious in most cases and the first symptoms are pain, swelling and stiffness in the joints.
  • the characteristic feature of RA is persistent inflammatory peripheral arthritis but also various extra-joint manifestations may be seen such as rheumatoid nodules, vasculitis, pulmonary fibrosis, neurological manifestations and Felty's syndrome.
  • RA causes the loss of joint motility and can make accomplishing simple task difficult.
  • RA has a substantial social effect in terms of cost, disability lost of quality of life and lost productivity.
  • RA affects about 1% of the population in a female/male ration of 3/1. Only in the United States, about two million people suffer from RA. The disease can occur at any age but about 80% of people with RA are diagnosed between ages 35-50 and its incidence is increasing with age. The lack of test that can absolutely diagnose RA leads to a several month delay before a firm diagnosis of RA can be ascertained.
  • RA disease modifying anti-rheumatic drugs
  • DMARDs disease modifying anti-rheumatic drugs
  • All of the DMARDs have significant toxic side effects, which require healthcare professionals to carefully compare the risks associated with these medications versus the benefits.
  • the methotrexate doses used in treatment of RA are small (7 to 20 g once weekly), but they may sometimes be associated with severe adverse effects, such as hepatic fibrosis or pneumonitis. Despite 50 to 80 % of the patients undergoing the methotrexate treatment have long- term stabilization of functional status, durable remissions have never been reported.
  • RA can be successfully treated with COMPOUND I or a pharmaceutically acceptable salt thereof, e.g. SALT I.
  • COMPOUND I is 4-(4-methylpiperazin-l-ylmemyl)-N-[4-memyl-3-(4-pyridm-3-yl)pyrimidin-2- ylamino)phenyl]-benzamide having the formula I
  • compositions of COMPOUND I are pharmaceutically acceptable acid addition salts, like for example with inorganic acids, such as hydrochloric acid, sulfurie acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di- carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy ⁇ benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid,
  • the invention relates to the use of a pharmaceutically acceptable acid addition of COMPOUND I, preferably the monomethanesulfonate salt, especially the beta crystal form of said salt, for the manufacture of pharmaceutical compositions for the treatment of rheumatoid arthritis, especially severe rheumatoid arthritis.
  • a pharmaceutically acceptable acid addition of COMPOUND I preferably the monomethanesulfonate salt, especially the beta crystal form of said salt
  • SALT I is administered, however the dosages are expressed as the dose of COMPOUND I free base administered, e.g. for a 100 mg dose, 119.5 mg of SALT I being administered corresponding to 100 mg of COMPOUND I free base.
  • effective doses for example daily doses of about 100-1000 mg, e.g. 200 to 800 mg, preferably 200-600 mg, especially 400 mg of COMPOUND I, are administered to warm-blooded animals of about 70 kg bodyweight.
  • a starting dose of 400 mg daily can be recommended.
  • dose escalation can be safely considered and patients may be treated as long as they benefit from treatment and in the absence of limiting toxicities.
  • the invention relates also to a method for administering to a human subject suffering from rheumatoid arthritis, especially severe rheumatoid arthritis, COMPOUND I or a pharmaceutically acceptable salt thereof, which comprises administering a pharmaceutically effective amount of COMPOUND I or a pharmaceutically acceptable salt thereof.
  • the invention relates especially to such method wherein a daily dose of 100 to 1000 mg, 200 to 800 mg, especially 400-600 mg, preferably 400 mg of COMPOUND I, e.g. SALT I, is administered.
  • the invention relates also to said method for administering to a human subject suffering from rheumatoid arthritis, especially severe rheumatoid arthritis, COMPOUND I or a pharmaceutically acceptable salt thereof, which comprises administering a pharmaceutically effective amount of COMPOUND I or a pharmaceutically acceptable salt thereof to the human subject once daily for a period exceeding 3 months.
  • the invention also relates in a combination which comprises (a) COMPOUND I or a pharmaceutically acceptable salt thereof and (b) a therapeutic agent selected from the anti-rheumatoid arthritis drugs, most preferably a combination wherein the combination partners are present in synergistically effective amounts.
  • the anti-rheumatoid arthritis drug can be, but is not limited to, one or more of the following (most of them are commercially available):
  • NSACD non steroidal anti-inflammatory drug
  • celecoxib, rofecoxib, valdecoxib (3) an anti-inflammatory steroidal drug such as 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, flupre
  • a gold salt such as gold sodium thiomalate, aurothioglycanide, calcium 3-aurothio-2-propanol-l- sulfonate, aurothioglucose, auranofin,
  • anti-malarial drugs such as chloroquine, hydroxychloroquine,
  • angiogenesis inhibitors monoclonal antibodies to adhesion molecules and growth factors, ICE inhibitors, 5-HT 3 receptor antagonists e.g. tropisetrone, p38 mitogen activated protein kinase inhibitors, matrix metalloproteinase inhibitors, lymphokine antagonists such as IL-1 receptor antagonists or anti-tumor necrosis factor ⁇ agents, e.g. etanercept, infliximab.
  • the combination partner (b) is an anti-inflammatory steroidal drug, most preferably, prednisone.
  • the effective dosage of each of the combination partners employed in the combination may vary depending on a variety of factors including the particular combination of the pharmaceutical compound partners, the route of administration, the severity of the disease, the renal and hepatic functions of the patient.
  • the molar ratio (a)/(b) of the combination partners is about 0.1 to 10, most preferably 0.3 to 3.
  • the unit dosage form contains the monomethanesulfonate salt of 4-(4- methylpiperazin-l-ylmethyl)-N-[4-memyl-3-(4-pvridin-3-yl)pyrir din-2-ylamino)phenyl]-benzamide of the formula I, most preferably in the beta crystal form at a dose corresponding to 20 to 200 mg, preferably 50 to 150 mg of COMPOUND I free base.
  • Example 1 Findings in a single patient with severe RA treated with COMPOUND I. e.g. SALT I
  • a patient who had concomitant rheumatoid arthritis and metastatic gastrointestinal tumor to the liver was treated with SALT I at a daily dose corresponding to 600 mg of COMPOUND I free base.
  • the patient was diagnosed with mesangial glomerulonephritis in 1988, and she also had the diagnoses of hypertension and Crohn's disease (ileitis terminalis). Her joint movements were severely limited due to persistent RA, but she was able to walk without walking aids.
  • the study drug SALT I is added on the anti-rheumatic medication which the patient is taking at the onset of the study. However, those anti-rheumatic drugs which can be suspected to have drug interactions with SALT I, are discontinued before the beginning of the study.
  • the starting dose of the drug will be 200 mg (SALT I is administered at a dose corresponding to 200 mg of COMPOUND I free base) once daily. If no severe adverse events (grade 3 or 4 according to the NCI toxicity criteria) occur the dose of SALT I will be increased to 300 mg at the beginning of the study week three and then to 400 mg once per day in the beginning of week 5, which dose is used until the end of the study unless grade 3 or 4 toxicity is encountered.
  • grade 3 or 4 toxicity occurs at the dose level 400 mg day, the study medication is withheld until grade 1 or less, and then resumed at the dose of 300 mg/day, and if such toxicity occurs at the dose level 300 mg/day, SALT I is resumed at the dose of 200 mg/day. If grade 3 or 4 toxicity occurs at the dose of 200 mg/day, the patient is removed from the study.
  • the study is planned to last 12 weeks. During that time the patients have a screening visit (baseline) and a total of 4 follow-up visits (weeks 2, 4, 8, and 12). On each visit complete physical check up is performed (including blood pressure, pulse, body weight) and the following parameters will be assessed:
  • VAS visual analog pain scale
  • A. hematologogy hemoglobin, total BC count, a differential count including neutrophils, lymphocytes, monocytes, eosinophils and basophils
  • B. blood chemistry creatinine, uric acid, albumin, total protein, total bilirubin, alkaline phophatase, AST, ALT, LDH
  • AnX-r ⁇ y of the hands is taken before starting SALT I, (d. -7 to 0) and after 12 weeks of treatment.
  • Synovial fluid aspiration If the patient has synovitis in the knee joint which requires synovial fluid aspiration samples are be taken from the synovial fluid to determine the SCF level, mast cell tr ptase level, and the activity of the synovial fluid matrix metalloproteinases.
  • a synovia biopsy may be taken at baseline within 2 weeks before starting SALT I, and repeated 2 to 3 months after enrollment (optional).
  • the study is an open label, prospective study on the efficacy and safety of SALT I, in the treatment of active severe rheumatoid arthritis.
  • Rheumatoid arthritis is required to be refractory to prior therapies including methotrexate at a dose of 10 mg or higher per week given with a glucocorticoid, and with at least one other disease modifying anti-rheumatic drug (DMARD).
  • Other inclusion criteria included a swollen joint count > 6, and at least 2 of the following 3 findings: 1) the tender joint count > 6, 2) a serum C-reactive protein (CRP) level > 15 mg/1 or the blood erythrocyte sedimentation rate (ESR) > 28 mm/h, or 3) significant morning stiffness lasting at least for 45 minutes.
  • CRP serum C-reactive protein
  • ESR blood erythrocyte sedimentation rate
  • the oral glucocorticoid dose is required to be 15 mg or less of prednisone or equivalent.
  • Cytostatic drugs considered to have potential interactions with SALT I are discontinued at least 4 weeks before the study entry. These include methotrexate and cyclophosphamide (Patient no. 3).
  • methotrexate and cyclophosphamide are discontinued at least 4 weeks before the study entry. These include methotrexate and cyclophosphamide (Patient no. 3).
  • methotrexate and cyclophosphamide Patient no. 3
  • One male and 2 female patients had failed methotrexate with severe erosive seropositive rheumatoid arthritis resistant to DMARDs fulfilling the revised criteria of the American College of Rheumatology are enrolled (Arnett F.C. et al., 1988, Arthritis Rheum. 31 :315-24).
  • Their mean age is 56 years (range, 41 to 64).
  • One patient (Patient 3) is HLA- B27 positive and has a history of bilateral sacroilitis, but he has no signs of active spine disease. This patient has also secondary Sj ⁇ gren's syndrome with positive speckled antinuclear antibodies.
  • SALT I is given orally as 100 mg capsules (119.5 mg of SALT I are administered and correspond to 100 mg of the free base form of COMPOUND I) with food.
  • a dose-escalation scheme is used. The starting dose is 200 mg per day for 2 weeks given as one 100 mg capsule taken in the morning and another in the afternoon. The dose is escalated to 300 mg/day for study weeks 3 and 4, and further to 400 mg per day for the study weeks 5 to 12.
  • the study duration is defined as 12 weeks, but the study protocol was later amended allowing those patients who benefited from SALT I, treatment to continue the treatment longer than for 12 weeks.
  • Another patient used hydroxychloroquine (300 mg per day) concomitantly with SALT I.
  • Intra-articular corticostreroid injections are allowed during the study if clinically indicated.
  • Two patients received intra-articular injections of short-acting glucocorticoids during the first 2 study months.
  • One patient (Patient 2) had 6 joints another one (Patient 1) 2 joints injected. The injected joints were omitted from efficacy analyses.
  • the primary efficacy measures were: change in the number of tender and swollen joints among the 66 diarthrodial joints, patient assessed pain and disease activity as estimated using the visual analogue scales (VAS), change in the blood erythrocyte sedimentation rate (ESR) and the serum C-reactive protein (CRP) level, and change in the health assessment questionnaire (HAQ) score.
  • VAS visual analogue scales
  • ESR blood erythrocyte sedimentation rate
  • CRP serum C-reactive protein
  • HAQ health assessment questionnaire
  • the HAQ score reflects the patient functional ability (Triggiani M. et ah, Lit. Arch. Allergy Appl. Immunol. 1989, 88:253-5) and a high score indicates a high degree of disability. Serum CRP and blood ESR are measured prior to the study and on the study weeks 2, 4, 8, and 12.
  • Rheumatoid arthritis of all 3 patients responded favorably to SALT I treatment.
  • the swollen joint counts, serum CRP levels, and the patient-assessed disease activity and pain levels decreased, and the blood erythrocyte sedimentation rate improved.
  • Both patients who completed the study period preferred not to discontinue SALT I, after the 12-week use of the drug.
  • Patient no. 3 has used SALT I for 24 weeks, and his rheumatoid arthritis status has continued to improve with a further decrease in the number of swollen joints (from 19 at 12 weeks to 15 at 24 weeks).
  • Example 3 Capsules with4-r(4-methyl-l-piperazin-l-ylmethylVN-r4-methyl-3-[ ' f4-(3-pyridinyl ' )-2- pyrimidinyl]amino]phenyl " jbenzamide monomethanesulfonate. ⁇ -crvstal form
  • the capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Electrical Discharge Machining, Electrochemical Machining, And Combined Machining (AREA)
  • Liquid Crystal Substances (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Il est possible d'utiliser 4-(4-méthylpipérazin-1-ylméthyl)-N-[4-méthyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phényl]-benzamide correspondant à la formule (I) ou un sel de cette substance, acceptable du point de vue pharmaceutique, pour traiter la polyarthrite rhumatoïde. Cette invention a également trait à l'association du composé correspondant à la formule (I) ou d'un de ses sels acceptable du point de vue pharmaceutique avec un ou plusieurs médicaments modifiant l'évolution de la polyarthrite rhumatoïde.
PCT/EP2003/000802 2002-01-28 2003-01-27 Traitement de la polyarthrite rhumatoide WO2003063844A2 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
EP03704474A EP1471916B1 (fr) 2002-01-28 2003-01-27 Traitement de la polyarthrite rhumatoide avec imatinib
BR0307286-0A BR0307286A (pt) 2002-01-28 2003-01-27 Tratamento de artrite reumatóide usando imatinib
NZ534137A NZ534137A (en) 2002-01-28 2003-01-27 Treatment of rheumatoid arthritis using monomethanesulfonate salt of imatinib
DK03704474T DK1471916T3 (da) 2002-01-28 2003-01-27 Behandling af rheumatoid arthritis under anvendelse af imatinib
US10/502,534 US20060264443A1 (en) 2002-01-28 2003-01-27 Treatment of rheumatoid arthritis
SI200331369T SI1471916T1 (sl) 2002-01-28 2003-01-27 Zdravljenje revmatoidnega artritisa z imatinibom
KR1020047011580A KR101030416B1 (ko) 2002-01-28 2003-01-27 류마티스성 관절염의 치료
JP2003563538A JP4398731B2 (ja) 2002-01-28 2003-01-27 関節リウマチの処置
CA2473158A CA2473158C (fr) 2002-01-28 2003-01-27 Traitement de la polyarthrite rhumatoide
DE60321888T DE60321888D1 (fr) 2002-01-28 2003-01-27
MXPA04007309A MXPA04007309A (es) 2002-01-28 2003-01-27 Tratamiento de artritis reumatoide.
ZA2004/05323A ZA200405323B (en) 2002-01-28 2004-07-05 Treatment of rheumatoid arthritis using imatinib
IL162983A IL162983A (en) 2002-01-28 2004-07-12 Use of imatinib for the manufacture of pharmaceutical compositions for the treatment of rheumatoid arthritis
NO20043585A NO328255B1 (no) 2002-01-28 2004-08-27 Anvendelsen av 4-(4-metylpiperazin-1-ylmetyl)-N-[4-metyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)fenyl]-benzamid og kombinasjoner av denne forbindelsen for fremstilling av preparater for behandling av reumatoid artritt.
HK05103443A HK1072192A1 (en) 2002-01-28 2005-04-21 Treatment of rheumatoid arthritis using imatinib
US12/328,013 US20090131382A1 (en) 2002-01-28 2008-12-04 Treatment of rheumatoid arthritis using imatinib

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0201882.8 2002-01-28
GBGB0201882.8A GB0201882D0 (en) 2002-01-28 2002-01-28 Organic compounds

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/328,013 Continuation US20090131382A1 (en) 2002-01-28 2008-12-04 Treatment of rheumatoid arthritis using imatinib

Publications (2)

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WO2003063844A2 true WO2003063844A2 (fr) 2003-08-07
WO2003063844A3 WO2003063844A3 (fr) 2004-04-01

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PCT/EP2003/000802 WO2003063844A2 (fr) 2002-01-28 2003-01-27 Traitement de la polyarthrite rhumatoide

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US (2) US20060264443A1 (fr)
EP (1) EP1471916B1 (fr)
JP (1) JP4398731B2 (fr)
KR (1) KR101030416B1 (fr)
CN (1) CN1646130A (fr)
AT (1) ATE399555T1 (fr)
BR (1) BR0307286A (fr)
CA (1) CA2473158C (fr)
DE (1) DE60321888D1 (fr)
DK (1) DK1471916T3 (fr)
ES (1) ES2309299T3 (fr)
GB (1) GB0201882D0 (fr)
HK (1) HK1072192A1 (fr)
IL (1) IL162983A (fr)
MX (1) MXPA04007309A (fr)
NO (1) NO328255B1 (fr)
NZ (1) NZ534137A (fr)
PL (1) PL212137B1 (fr)
PT (1) PT1471916E (fr)
RU (1) RU2322238C2 (fr)
SI (1) SI1471916T1 (fr)
WO (1) WO2003063844A2 (fr)
ZA (1) ZA200405323B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1487451A1 (fr) * 2002-03-21 2004-12-22 Dana-Farber Cancer Institute, Inc. Inhibition de reponses de mort cellulaire induite par stress oxydatif
WO2005053696A1 (fr) * 2003-11-21 2005-06-16 Kari Kalervo Eklund Traitement de spondylarthropathies
WO2007143146A2 (fr) * 2006-05-31 2007-12-13 The Board Of Trustees Of The Leland Stanford Junior University Procédé de traitement de maladies inflammatoires utilisant des inhibiteurs de tyrosine kinase
WO2013191401A1 (fr) 2012-06-18 2013-12-27 아주대학교산학협력단 Composition pour le traitement ou la prévention de maladies causées par une perméabilité vasculaire, contenant de l'imatinib ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

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PT1805510E (pt) * 2004-09-08 2012-04-27 Immunaid Pty Ltd Estratégia terapêutica para o tratamento de doenças autoimunes e doenças degenerativas
CN102512421B (zh) * 2011-10-28 2013-11-06 中国科学院广州生物医药与健康研究院 哌嗪酰胺类化合物在制药中的应用
RU2580656C1 (ru) * 2014-11-20 2016-04-10 Закрытое Акционерное Общество "БИОКОМ" Твердая лекарственная форма гидроксихлорохина немедленного высвобождения и способ ее получения
US12173065B2 (en) * 2018-10-18 2024-12-24 Sinomab Bioscience Limited Fusion proteins comprising extracellular domain of human CD22

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EP1487451A1 (fr) * 2002-03-21 2004-12-22 Dana-Farber Cancer Institute, Inc. Inhibition de reponses de mort cellulaire induite par stress oxydatif
EP1487451A4 (fr) * 2002-03-21 2007-10-03 Dana Farber Cancer Inst Inc Inhibition de reponses de mort cellulaire induite par stress oxydatif
WO2005053696A1 (fr) * 2003-11-21 2005-06-16 Kari Kalervo Eklund Traitement de spondylarthropathies
WO2007143146A2 (fr) * 2006-05-31 2007-12-13 The Board Of Trustees Of The Leland Stanford Junior University Procédé de traitement de maladies inflammatoires utilisant des inhibiteurs de tyrosine kinase
WO2007143146A3 (fr) * 2006-05-31 2009-07-23 Univ Leland Stanford Junior Procédé de traitement de maladies inflammatoires utilisant des inhibiteurs de tyrosine kinase
WO2013191401A1 (fr) 2012-06-18 2013-12-27 아주대학교산학협력단 Composition pour le traitement ou la prévention de maladies causées par une perméabilité vasculaire, contenant de l'imatinib ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

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NO20043585L (no) 2004-10-21
PT1471916E (pt) 2008-10-03
CN1646130A (zh) 2005-07-27
IL162983A (en) 2010-06-16
ATE399555T1 (de) 2008-07-15
RU2004126447A (ru) 2005-07-10
WO2003063844A3 (fr) 2004-04-01
US20090131382A1 (en) 2009-05-21
PL212137B1 (pl) 2012-08-31
JP2005526022A (ja) 2005-09-02
BR0307286A (pt) 2004-12-28
US20060264443A1 (en) 2006-11-23
PL370264A1 (en) 2005-05-16
ES2309299T3 (es) 2008-12-16
RU2322238C2 (ru) 2008-04-20
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NZ534137A (en) 2007-03-30
DE60321888D1 (fr) 2008-08-14
KR101030416B1 (ko) 2011-04-20
EP1471916A2 (fr) 2004-11-03
DK1471916T3 (da) 2008-10-20
HK1072192A1 (en) 2005-08-19
KR20040086301A (ko) 2004-10-08
CA2473158C (fr) 2013-06-11
NO328255B1 (no) 2010-01-18
SI1471916T1 (sl) 2008-12-31
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MXPA04007309A (es) 2005-09-12
JP4398731B2 (ja) 2010-01-13
EP1471916B1 (fr) 2008-07-02

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